Aggravated Atherosclerosis and Vascular Inflammation With Reduced Kidney Function Depend on Interleukin-17 Receptor A and Are Normalized by Inhibition of Interleukin-17A

Visual Abstract

The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics

Abstract Background The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials. Methods In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Me…

Surface-bound bovine serum albumin carrier protein as present in recombinant cytokine preparations amplifies T helper 17 cell polarization

AbstractUnderstanding of T helper 17 lineage (TH17) polarization has been significantly promoted by cell culture experiments that reduce the complexity of the in vivo environment. We here investigated TH17 amplification by coating of cytokine preparations. Cytokine preparations coated to the surface compared to the same amount given in solution significantly enhanced TH17 polarization assessed by flow cytometry and interleukin (IL)-17A, IL-17F and RORγt mRNA expression. T cell proliferation and TH1 polarization were similarly enhanced while TREG polarization was impeded. TH17 amplification was replicated by coating the plate with low amounts of FCS or albumin as used as carrier protein for …

Author response: Notch and TLR signaling coordinate monocyte cell fate and inflammation

Reappraisal of European guidelines on hypertension management: A European Society of Hypertension Task Force document

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Commit

Notch and TLR signaling coordinate monocyte cell fate and inflammation

AbstractConventional Ly6Chi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6Chi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6Clo monocyte development. At the same time, TLR7 stimulation in the absence of …

Figure 3: IL-17 Receptor A Increases Atherosclerotic Inflammation in Renal Impairment

LDLr–/– and Il17ra–/–LDLr–/– mice were kept on a high-fat diet for 10 weeks after RI or ctrl surgery. (A to F) Aortic leukocytes were analyzed by using flow cytometry for all leukocytes (CD45), myeloid cells (CD11b), B cells (CD19), and T cells (αβ-T-cell receptor [TCR]). (A and D) Typical examples with CD11b+ myeloid cells among all leukocytes are shown in the upper rows and T cells and B cells among all nonmyeloid cells in the lower rows. (B, C, E, F) All leukocytes (B and E) and among CD11b+ myeloid cells granulocytes (PMN, Gr1HIGHF4/80LOWCD11cLOW) and expression of macrophage marker F4/80 and antigen presenting cell markers CD11c and major histocompatibility complex (MHC) II were invest…

Figure 2: Aortic Root Lesion Formation in Renal Impairment Is Enhanced by IL-17 Receptor A

LDLr–/– and Il17ra–/–LDLr–/– male mice were kept on a high-fat diet for 10 weeks after RI or ctrl surgery. (A and B) Aortic root lesions were assessed by histology (typical examples, bar indicates 500 μm, and statistical analysis of n = 5 to 6 per group LDLr–/– mice and n = 4 to 5 Il17ra–/–LDLr–/– mice from 3 independent experiments, 2-way ANOVA, significant effects of treatment group [p < 0.0001] and distance [p < 0.0001], no significant interaction for A or B). (C) Aortic roots were stained for CD11b (green) and CD11c (red) with nuclear counterstain (4',6-diamidino-2-phenylindole [DAPI], blue) (typical examples, 10× and 20× original magnification, bars indicate 500 and 250 μm, respe…

Figure 6: IL-17A Blockade Normalizes Inflammation in Established Atherosclerotic Lesions in Renal Impairment

(A to E)LDLr–/– mice after RI or ctrl were kept on a high-fat diet for a total of 12 weeks after RI. After 6 weeks, they were treated with anti–IL-17A antibody or isotype control. (B and C) Atherosclerotic root lesion size was assessed by histology (B, examples and [C] statistical analysis of n = 7 to 8 per group from 3 to 4 independent experiments, 2-way ANOVA, significant effects of treatment group [p = 0.018] and distance [p < 0.0001], no significant interaction). (D) Aortic roots were stained for CD11b (green) and CD11c (red) with nuclear counterstain (DAPI, blue) (typical examples, 10× and 20× original magnification, bars indicate 500 μm). (E) Flow cytometry of aortic leukocytes was…

Figure 1: IL-17 Receptor A Increases Advanced Atherosclerotic Lesion Size in Renal Impairment

(A to G)LDLr–/– and Il17ra–/–LDLr–/– male mice were kept on a high-fat diet for 20 weeks after unilateral nephrectomy (RI) or control (ctrl) surgery. (B to D) En face atherosclerotic lesion size was analyzed in the total aorta (C) and the aortic arch (D) (n = 5 to 6 per group from 2 independent experiments, Bonferroni after analysis of variance [ANOVA]). (E to G) Aortic root lesions were assessed by histology (E, typical examples, bar indicates 500 μm; F, statistical analysis of mean lesion size by Bonferroni after ANOVA). (G) Lesion according to longitudinal distance (2-way ANOVA, significant effects of treatment group [p < 0.0001] and distance [p < 0.0001], no significant interactio…

Figure 5: IL-17A Promotes Inflammatory Cytokine Expression in Endothelial Cells

(A) IL-17 receptor A (Il17ra) and auxiliary subunits Il17rc and Il17re mRNA expression was determined by using quantitative polymerase chain reaction (qPCR). Il17rb messenger ribonucleic acid (mRNA) was below detection limit (n = 4, 2 exp.). (B to I) Endothelial cells were stimulated for 2 h with 50 ng/ml IL-17A (B to E) or IL-17F (F to I). CCL2 (B and F), CXCL1 (C and G), IL-6 (D and H), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (E and I) cytokine expression quantified by using qPCR (n = 8 from 4 independent experiments for each cytokine).

Figure 4: Role of Myeloid Cell IL-17 Receptor A in Aortic Inflammation

(A and B) IL-17 receptor A expression was determined by flow cytometry on aortic CD45+ leukocytes with and without the myeloid cell marker CD11b (A, n = 3 to 8) and blood leukocytes (B, n = 6 to 7 [2 independent experiments each]) data are expressed as mean fluorescence intensity (MFI), identically treated Il17ra–/– cells are shown as negative controls for comparison, Student t tests). (C and D) Aortic arches from Il17a–/– and Il17ra–/– mice were co-incubated for 1 h with myeloid cells from Il17a–/– or Il17ra–/– mice in the presence or absence of 50 ng/ml IL-17A and aortic myeloid cell content determined by using flow cytometry (n = 4 to 6 from 4 independent experiments, aortic live CD11b+ …